Compositions containing benzodiazepindiones and method of use

ABSTRACT

Compositions containing 1,2,3,11a-tetrahydro-10-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5,11(10H)-dione in the form of its dextrorotatory isomer and as a racemic mixture and method of use are described. The active component in its different forms is useful in treating anxiety in warm-blooded animals.

This application is a continuation-in-part of my application Ser. No.464,424, filed Apr. 26, 1974 now abandoned.

DESCRIPTION OF THE INVENTION

This invention relates to new compositions and method of use in itsdextrorotatory or racemic form of 1,2,3,11a-tetrahydro-10-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5,11(10H)-dione.

The active component of the novel compositions of the present inventionmay be illustrated by the following formula: ##SPC1##

This compound is a solid at room temperature, soluble in methanol,ethanol, benzene, acetone and ethyl acetate, but having limitedsolubility in hexane and water, the dextrorotatory isomer having anoptical rotation [α]_(D) ²⁵ of +486° at a concentration of 1% inmethanol and a melting point of 120°-122°C.

The compounds of this invention may be prepared by the following methodwhich has been found most desirable. ##SPC2##

N-Methyl isatoic anhydride (I) and L-proline (II) are reacted in asolvent such as ethanol or dimethyl sulfoxide at 25° to 200°C. for aperiod of 1 to 24 hours to produce the dextrorotatory isomer of1,2,3,11a-tetrahydro-10-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5,11(10H)-dione.

Alternatively, the dextrorotatory isomer may be prepared by thefollowing two-step process involving the reaction of L(-)-proline andN-methyl isatoic anhydride to produce the intermediateL(-)-1-(N-methylanthraniloy)proline: ##SPC3##

N-Methyl isatoic anhydride (I) and L-proline (II) are reacted indimethyl sulfoxide for 20 to 120 minutes at 50° to 100°C. to produceL(-)-1-(N-methylanthraniloyl)proline (IV), which is recovered and thenheated in an oil bath at 145°C. to 200°C. for 10 to 60 minutes toproduce the dextrorotatory isomer (III).

Cyclization may also be carried out by contacting theL(-)-1-(N-methylanthraniloyl)proline (IV) with a condensing agent suchas thionyl chloride, N,N'-carbonyldiimidazole, dicyclohexylcarbodiimideor the like.

The recemic (DL) form of this compound may be prepared by substitutingDL-proline in any of these reactions.

As an alternative to the second method, the same starting material maybe reacted in dimethylsulfoxide at 25° to 200°C. for 1 to 24 hours toproduce the subject dextrorotatory isomer.

In still another method, N-methylisatoic anhydride (I) is first reactedwith an ester of proline (V) to form an intermediate1-(N-methylanthraniloyl)proline ester (VI) which is then cyclized to IIIby heating, by heating under acidic or alkaline conditions or byreacting in the presence of an amide forming reagent. ##SPC4##

Wherein R is hydrogen, alkyl C₁ -C₁₀, or benzyl and the like.Alternatively, other agents such as N-methylanthranilic acid, acidchloride, esters or anhydride may be similarly condensed with proline orproline ester and cyclized.

The active component can also be prepared by the alkylation of theanalogous desmethyl compound in the presence of an alkali catalyst. Forexample, a mixture of1,2,3,11a-tetrahydro-5H-pyrrolo[2]-benzodiazepin-5,11(10H)-dione (VIII),sodium methoxide, ethanol and methyliodide is allowed to react at roomtemperature for 24 hours and the desired compound (III) is then removed.##SPC5##

The following method can also be used to prepare the compounds of thisinvention (III) by the cyclization ofN-(pyrrolidine-2-carbonyl)anthranilic acid or its esters (VIII) byheating with or without an alkaline catalyst such as sodium methylate ata temperature of about 150°-210°C. or by treating with an amide formingcyclizing agent such as thionyl chloride, N,N'-carbonyldiimidazole, ordicyclohexylcarbodiimide. ##SPC6##

where R is hydrogen, alkyl C₁ -C₁₀ or benzyl and the like.

The active components of the present invention possess central nervoussystem activity at non-toxic doses, and as such, are useful asanxiolytic agents. The compounds have been tested pharmacologically andfound to have the above properties which show a desirable wide spreadbetween doses producing anxiolytic activity and toxic symptoms.Depressant properties are absent at effective anxiolytic doses.

The anti-anxiety properties of the active components of the presentinvention have been established in a test which indicates anxiolyticactivity by a measure of protection from convulsions resulting from theadministration of pentylenetetrazol. Graded dose levels of the dextroand racemic forms of the compound1,2,3,11a-tetrahydro-10-mthyl-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5,11(10H)-dione are administered orally, in a 2%starch vehicle, to groups of at least 5 rats. At the estimated time ofpeak effect, the rats are treated intravenously with pentylenetetrazoleat a dose of 21 to 23 mg./kg. of body weight. This dose is estimated tocause clonic seizures in 99% of unprotected rats. The effective dose ofthe test compound for protection of 50% of the animals is calculated bythe method of J. T. Litchfield and F. Wilcoxon, Journal of Pharmacologyand Experimental Therapeutics, 96, 99 (1949). The results are given inthe table which follows in comparison with Librium (chlordiazepoxide),Valium (diazepam) and the dextro and racemic forms of 1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c] [1,4]benzodiazepin-5,11(10H)-dione (U.S.Pat. No. 3,732,212) all of which were tested in exactly the same manner.It has been reported [R. T. Hill and D. R. Tedeschi, "Animal Testing andScreening Procedures in Evaluating Psychotropic Drugs" in AnIntroduction to Psychopharmacology, Eds. R. R. Rech and K. E. Moore,Raven Press, New York, pp. 237-288 (1971) that there is a high degree ofcorrelation between antagonism of pentylenetetrazole seizures in ratsand antianxiety effects in higher warm-blooded animals.

                                      TABLE                                       __________________________________________________________________________    Protection Against Clonic Seizures Caused by Pentylenetetrazole               In Rats                                                                       __________________________________________________________________________                                Median Effective Oral Dose                                Compound            (mg/kg) ED.sub.50                                 __________________________________________________________________________    1.                                                                              Dextro-1,2,3,11a-tetrahydro-10-methyl-5H-                                                               10                                                pyrrolo[2,1-c][1,4]benzodiazepin-5,11(10H)-                                     dione                                                                       2.                                                                              Racemic-1,2,3,11a-tetrahydro-10-methyl-5H-                                                              20                                                  pyrrolo[2,1-c][1,4]benzodiazepin-5,11(10H)-                                   dione                                                                       3.                                                                              Dextro-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c]-                                                          35                                                  [1,4]-benzodiazepin-5,11(10H)-dione                                         4.                                                                              Racemic-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c]-                                                         70                                                  [1,4]benzodiazepin-5,11(10H)-dione                                          5.                                                                              Librium (chlordiazepoxide)                                                                              2.5                                               6.                                                                              Valium (diazepam)         1.8                                               __________________________________________________________________________

It can be seen from the above results that the dextrorotatory andracemic forms of 1,2,3,11a-tetrahydro-10-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5,11(10H)-dione (Compounds 1 and 2) are far moreeffective as anxiolytic agents than the respective dextrorotatory andracemic forms of the closest prior art compound1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5,11(10H)-dione (Compounds 3 and 4).

The active components of the present invention may be administered towarm-blooded animals, in either its dextrorotatory or racemic forms,orally, or parenterally if desired, and when so administered, may beconsidered as a tranquilizing agent for therapeutically desiredtreatment of anxiety in warm-blooded animals. The dosage regimen can beadjusted to provide optimum therapeutic response. Thus, for example,several doses may be administered daily, or the dose may be reducedproportionately as indicated by the requirements of the particulartherapeutic situation.

For therapeutic administration the active compound of this invention maybe incorporated with pharmaceutical carriers such as excipients andused, for example, in the form of tablets, dragees, capsules, liquids,elixirs, emulsions, suspensions, syrups, chocolate, candy, wafers,chewing gum or the like for oral administration.

Parenteral solutions and suspensions may be prepared for intramuscularor subcutaneous administration, and suppositories may be prepared forrectal administration. Such compositions and preparations should containat least 0.1% of active component. The percentage of the compositionsand preparations may, of course, be varied, and may conveniently bebetween 2 to 60% or more of the weight of the unit. The amount of activecomponent in such therapeutically useful compositions or preparations issuch that a suitable dosage of from about 1.0 to about 10.0 mg/kg/dayfor the dextrorotatory isomer and from about 2.0 to about 25.0 mg/kg/dayfor the racemic mixture will be obtained. Preferred compositions orpreparations according to the present invention are prepared so that adosage unit form contains between about 20 and about 300 mg. of thetherapeutically active component.

The compositions of this invention are physiologically active asanxiolytic agents. As such, they can be incorporated in variouspharmaceutical forms such as set forth immediately above, for immediateor sustained release, by conbining with suitable pharmaceutical carriersThey may be in the form of dosage units for a single therapeutic dose orin small units for multiple dosages or in larger units for division intosingle doses. Obviously, in addition to the therapeutic tranquilizingcompound there may be present excipients, binders, fillers and othertherapeutically inert ingredients necessary in the formulation of thedesired pharmaceutical preparation.

SPECIFIC DISCLOSURE

The following specific examples illustrate the preparation of thecompounds of the present invention along with formulations of the activecomponent. Parts are by weight unless otherwise indicated.

EXAMPLE 1 Preparation of Dextrorotatory1,2,3,11a-Tetrahydro-10-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5,11(10H)-dione 1

A mixture of 17.7 g. of N-methyl isatoic anhydride, 11.5 g. of L-prolineand 250 ml. of ethanol is heated on a steam bath for 3 hours and thenconcentrated to remove the ethanol. The residue is mixed with benzeneand a small portion of water and the layers are separated. The benzenelayer is washed twice with water and concentrated to remove the solvent.The residue is triturated with ether. The crystals which form arecollected by filtration and recrystallized from ethyl acetate yieldingthe pure dextrorotatory isomer, melting point 120°-122°C., [α]_(D) ²⁵ +486°(1%, methanol).

EXAMPLE 2 Preparation of Racemic (DL)1,2,3,11a-Tetrahydro-10-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5,11(10)-dione

The racemic compound is obtained by substituting DL-proline in place ofL-proline in the procedure of Example 1. The racemate melts at124°-126°C.

EXAMPLE 3 Preparation of Dextrorotatory1,2,3,11a-Tetrahydro-10-methyl-5H-pyrrolo[2,1-c] [1,4]benzodiazepin-5,11(10H)-dione

A mixture of 12.3 g. of L-proline, 17.7 g. of N-mthyl isatoic anhydrideand 100 ml. of dimethyl sulfoxide is heated on a steam bath for 40minutes. The mixture is cooled and diluted with 250 ml. of cold water.The precipitate is recovered by filtration, washed with water and thenether, air dried and then recrystallized from ethanol yielding theintermediate L-1-(N-methylanthrailoyl)proline, melting point140°-142°C., [α]_(D) ²⁵ -165°C. (1.1%, methanol).

This intermediate is placed in a round bottom flask and immersed in anoil bath heated to 170°-180°C. for 30 minutes. The material is dissolvedin ethyl acetate and cooled. The desired dextrorotatory productseparates as crystals which are recovered by filtration.

EXAMPLE 4 Preparation of Dextrorotatory1,2,3,11a-Tetrahydro-10-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5,11(10H)-dione

A mixture of 12.3 g. of L-proline, 17.7 g. of N-methyl isatoic anhydrideand 100 ml. of dimethyl sulfoxide is heated on a steam bath for 6 hours,cooled and then dilted with 250 ml. of water. The reaction mixture isextracted three times with benzene. The combined benzene layers arewashed with water and concentrated to remove the solvent. The residue isrecrystallized from ethyl acetate yielding the pure dextrorotatoryisomer.

EXAMPLE 5

The present compounds can be dispensed in dosage unit forms such as hardshell capsules or soft shell capsules. A formulation found useful in thepreparation of such capsules is as follows:

                      Grams   Grams                                               Dextro-1,2,3,11a-tetrahydro-10-                                                                   25        --                                              methyl-5H-pyrrolo[2,1-c][1,4]-                                                benzodiazepin-5,11(10H)-dione                                                 Racemic-1,2,3,11a-tetrahydro-                                                                     --        50                                              10-methyl-5H-pyrrolo[2,1-c]-                                                  [1,4]benzodiazepin-5,11(10H)-                                                 dione                                                                         Lactose U.S.P.      3,000     3,000                                           Magnesium stearate (.0.5%)                                                                        31.25     31.25                                                               3,056.25  3,081.25                                    

The formulation is thoroughly mixed and placed as equal quantities in1000 capsules. Each capsule of either formulation represents about 25mg. of active component.

EXAMPLE 6

The following example represents a formulation useful in preparingtablets. These tablets can be prepared with sufficient active ingredientfor a portion of one days use. Larger tablets can be scored and dividedinto halves or quantities to be given one to four times per day.Obviously, smaller tablets can be used in multiple doses to obtain thedaily dose.

    ______________________________________                                                          Per Tablet                                                  Dextro-1,2,3,11a-tetrahydro-10-                                                                   50 mg.    --                                              methyl-5H-pyrrolo-[2,1-c][1,4]-                                               benzodiazepin-5,11(10H)-dione                                                 Racemic-1,2,3,11a-tetrahydro-                                                                     --        100 mg.                                         10-methyl-5H-pyrrolo-[2,1-c]-                                                 [1,4]benzodiazepin-5,11(10H)-                                                 dione                                                                         Corn Starch         420 mg.   420 mg.                                         Methylcellulose 400 700 mg.   700 mg.                                         Magnesium stearate (1%)                                                                           364 mg.   364 mg.                                                             1,534 mg. 1,584 mg.                                       ______________________________________                                    

Each tablet contains 50 mg. of the dextro or 100 mg. of the racemic formof the active component.

EXAMPLE 7

The active component of the present invention can also be given in theform of tablets made by other formulations such as:

                       Per Tablet                                                 Dextro-1,2,3,11a-tetrahydro-10-                                                                    25 mg.    --                                             methyl-5H-pyrrolo-[2,1-c][1,4]-                                               benzodiazepin-5,11(10H)-dione                                                 Racemic-1,2,3,11a-tetrahydro-                                                                      --        50 mg.                                         10-methyl-5H-pyrrolo[2,1-c][1,4]-                                             benzodiazepin-5,11(10H)-dione                                                 Corn Starch          300 mg.   300 mg.                                        Ethyl cellulose      5 mg.     5 mg.                                          Magnesium stearate   1.6 mg.   1.6 mg.                                                             331.6 mg. 356.6 mg.                                  

The above formulation can be varied by increasing or decreasing the cornstarch and by the addition of other ingredients. Also, otherdisintegrating agents, such as potato starch, may be used in place ofcorn starch. Other lubricants such as stearic acid, talc and the likecan be used. Sweetening agents such as saccharin or sodium cyclohexylsulfamate and flavoring such as peppermint oil, oil of wintergreen,orange or cherry can be used.

EXAMPLE 8 Preparation of Racemic1,2,3,11a-Tetrahydro-10-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5,11(10H)-dione

A mixture of 4.32 g. of 1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5,11(10H)-dione, 1.2 g. of sodium methylate and 40ml. of ethanol is stirred at room temperature for 3 houRS and 3 ml. ofmethyl iodide is added. The reaction mixture is stirred for 6 hourslonger and concentrated. The residue is mixed with benzene and water andthe layers are separated. The benzene layer is washed with water andconcentrated. The product is further purified by recrystallization fromethyl acetate and melts at 124°-126°C.

EXAMPLE 9 Preparation of Dextrorotatory1,2,3,11a-Tetrahydro-10-methyl-5H-pyrrolo[2,1-cl][1,4]benzodiazepin-5,11(10H)-dione

A mixture of 24.8 g. of (-)-1-(N-methylanthraniloyl)proline and 300 ml.of benzene is stirred and 12.0 g. of thionyl chloride is added dropwise.The mixture is heated at relux temperature for 2 hours, cooled, washedtwice with water and concentrated to recover the(+)-1,2,3,11a-tetrahydro-10-methyl-5H-pyrrolo[2,1c][1,4]benzodiazepin-5,11(10H)dione.

EXAMPLE 10 Preparation of Dextrorotatory1,2,3,11a-Tetrahydro-10-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5,11(10H)-dione

A mixture of 24.8 g. of (-)-1-(N-methylanthraniloyl)proline and 18.0 g.of N,N'-carbonyldiimidazole in 300 ml. of dry tetrahydrofuran is stirredfor 2 hours at room temperature and then heated at reflux temperaturefor 3 hours. The reaction mixture is concentrated to remove the solventand the residue is extracted into benzene. The benzene solution iswashed twice with water and concentrated to recover the desired product.

EXAMPLE 11 Preparation of Racemic1,2,3,11a-Tetrahydro-10-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5,11(10H)-dione

A mixture of 24.8 g. of racemic 1-(N-methylanthraniloyl)proline and 21g. of dicyclohexylcarbonyl diimide in 300 ml. of tetrahydrofuran isstirred at room temperature for 24 hours and then heated on the steambath for 4 hours. The reaction mixture is filtered to remove theinsoluble dicyclohexyl urea and the mother liquid is concentrated torecover the desired product, which is further purified byrecrystallization from ethyl acetate.

EXAMPLE 12 Preparation of Racemic1,2,3,11a-Tetrahydro-10-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5,11(10H)-dione

A mixture of 17.7 g. of N-methylisatoic anhydride, 15.0 g. of the ethylester of proline and 100 ml. of dimethylsulfoxide is heated on a steambath for 40 minutes. The mixture is cooled and diluted with 250 ml. ofcold water. The reaction mixture is extracted with benzene and thebenzene solution is concentrated to recover the ethyl ester of1-(N-methylanthraniloyl)proline.

Ten grams of the above ester is dissolved in 150 ml. of 2N ethanolichydrochloric acid and heated at reflux temperature for 8 hours. Thereaction mixture is concentrated to remove the solvent and the residueis purified by liquid chromatography using hexane/methanol and a celitecolumn.

The embodiments of the invention in which an exclusive property orprivilege is claimed are defined as follows:
 1. A method of treatinganxiety in a warm-blooded animal which comprises administeringinternally to said warm-blooded animal an anti-anxiety amount of1,2,3,11a-tetrahydro-10-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5,11(10H)-dione and a pharmaceutically acceptable carrier therefor.
 2. A methodaccording to claim 1, in which the active component is thedextrorotatory isomer of1,2,3,11a-tetrahydro-10-methyl-5H-pyrrolo[2,1-c][1,4-benzodiazepin-5,11(10H)-dione.3. The process according to claim 1, in which the active component isthe racemic mixture of1,2,3,11a-tetrahydro-10-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5,11(10H)dioneisomers.